Integrin Proteins


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 Integrin Proteins Background

Cell adhesion involves the interplay between Integrins and the adhesion complexes comprised of Integrin-associated multidomain proteins that function as direct Integrin-Actin linkers, of adaptors that interact with the Actin-bound or Integrin-bound components all together forming the physical structure of the adhesion site, and of enzymes that modify such interactions and trigger signaling cascades. Despite the vast molecular complexity, each of them has a unique function on Integrin-mediated adhesion.
The Integrin family of heterodimeric transmembrane receptors represents the nodal point that links the Actin cytoskeleton to the ECM. While their globular extracellular domain contributes to binding the ECM, their short cytoplasmic tail organizes the Actin cytoskeleton through Integrin-associated protein complexes, whose molecular composition will be discussed in the following sections. As such, Integrins are positioned to transmit the externally and internally developed forces across the plasma membrane as well as to convert these forces into chemical signals that ultimately alter many cellular behaviors.
The bidirectional aspect of Integrins controls Integrin function per se. Integrin adhesion to the ECM is accomplished through the action of intracellular signals (possibly generated by other cell receptors, such as Gprotein coupled receptors) and mechanical forces that increase similarly the affinity of the receptor for ligand. Force-induced conformational changes in Integrin structure constitute the basis of mechanosensing.
In their resting state prior to contact with the ECM, Integrin heterodimers, composed of an α and a β subunit, are mostly in an inactive conformation, with their extracellular domain in a bent conformation and the two very short cytoplasmic domains held together by a transmembrane noncovalent salt bridge. Cellular stimulation induces disruption of the clasp between α and β cytoplasmic tails, followed by a conformational change in the extracellular domains from a bent to a more extended form for a high affinity ligand binding. During this transition, the Integrin cytoplasmic tail also exposes the conserved regions for its binding partners that are required to establish contact with the Actin cytoskeleton. Following Actin organization, the cytoskeleton generates forces that are transmitted to Integrins, promoting their clustering. In turn, receptor aggregation increases Integrin avidity for ligand, thus strengthening Integrin adhesion. This model constitutes the mechanism of Integrin activation and clustering.
Functional analysis of Integrins in Drosophila has demonstrated their critical role in stable adhesion within muscles. Integrins arise through combinations of two β subunits and five α subunits. The attachment of embryonic muscles to the tendon matrix is accompanied by strong complem-entary expression of two Integrins, αPS1βPS and αPS2βPS, at the sites of attachment. αPS1 localizes at the ends of epidermal tendon cells, while αPS2 is restricted to the muscle ends. During embryogenesis, Integrins are not required to form the initial muscle-tendon contacts, which are presumably mediated by cell-cell adhesion molecules such as Cadherins, but to maintain the stable adhesions during muscle contractions. Indeed, mutations in myospheroid (mys) as well as in inflated (if), which encode βPS and αPS2, respectively, cause detachment of muscles from the tendon matrix soon after contraction begins.
It is quite likely that sarcomeregenesis and costamerogenesis depends on Integrins. Immunostaining of Integrins in cultured mouse cardiomyocytes demonstrates their distribution in costameric structures. An early study with Drosophila myoblast cells in culture lacking βPS or αPS2 Integrin has also pointed to a role for Integrins in sarcomere assembly. Later work showed that blocking αPS2 Integrins inhibits muscle attachment to the epidermis and sarcomeric organization as well. From these investigations, integrins appear to establish the cytoskeletal link to the sarcolemma.
A large body of evidence implicates Integrins in sensing mechanical forces. Analysis of mechanosensing in vitro generally relies on the culturing of cells on matrix coated silicone membranes. Mechanical force modifies affinity of Integrins for the ECM ligand and these alterations can easily be observed by phase contrast microscopy as wrinkles in silicone rubber substrates. In addition, Integrins localized at costameres, mediate assembly of their ECM ligands in a costameric-like pattern. Collectively, these data indicate that mechanical stretch-induced conformational activation of Integrins with subsequent clustering potentiates the cell matrix adhesion.
Other studies demonstrate the unquestionable role of Integrins in mechanotransduction. Integrins are also sites for localization of signaling molecules. Because the cytoplasmic tail of Integrins lacks endogenous catalytic activity, they signal by associating with protein kinases and GTPases such as focal adhesion kinase (FAK), Integrin linked kinase (ILK), and protein kinase C (PKC). Results obtained in mechanically stressed cultured cells and pressure-overload studies in intact myocardium have revealed rapid activation of downstream Integrin effectors in response to mechanical changes. Of note, FAK is rapidly phosphorylated/activated by mechanical stretch in rat cardiomyocytes. Moreover, stretch-induced activation of PKC initiates a cascade of growth (hypertrophic) response in cardiomyocytes. These findings implicate FAK, PKC and Integrin in functioning as a sensory/signaling complex in muscle. Therefore, Integrins represent an interface between sensing and signaling.